Health Status of Childhood Cancer Survivors: Title and subTitle BreakCure Is More Than the Eradication of Cancer

Children with cancer become adults who had cancer. Cancer occurs in approximately 1 of 300 to 350 young people before age 20 years in the United States, a seemingly small number compared with the number of adults afflicted with cancer.¹ Yet with 5-year, event-free survival rates exceeding 75%,² 1 of 500 young adults (aged 20-35 years) in the United States have had a diagnosis of cancer before age 20 years. As these individuals become adults, the cancer diagnosis may recede into the past, but the long-term effects on health and perceived health status continue into the future. It is not uncommon to speak of curing cancer, but cure is the restoration of health. While cancer can be eradicated, survivors must be restored to health that lasts for decades. Five-year survival is only the beginning, not the end point of successful treatment.

In this issue of THE JOURNAL, Hudson et al³ compared the self-reported health status of 9535 young adult survivors in the Childhood Cancer Survivor Study with that of 2916 siblings. The 6 domains of health status evaluated included general health, mental health, functional status, and activity limitations in all participants, with cancer-related pain and anxiety/fears assessed only in survivors. In all domains compared, all survivors and survivors of each disease were significantly more likely to report adverse outcomes. This finding is not surprising because cancer therapy is known to affect virtually every body organ, including cardiac toxicity after anthracycline exposure, myocardial ischemia after chest radiation, infertility after alkylating agent exposure, pulmonary dysfunction after bleomycin exposure, renal and ototoxicity after cisplatin exposure, and secondary malignancy after radiation, alkylating agents, and etoposide.⁴ If cure is the restoration of health, by definition individuals affected by adverse sequelae are not truly cured.

This study differs from most investigations of long-term outcomes because adverse health status is that which is perceived by the survivors. Patients cannot detect subclinical injury. Nonetheless, critical information for understanding the psychological and behavioral responses to survival is revealed by self-report, the only method that can realistically be used for an epidemiologic study of this magnitude. Perception of risk and of cancer treatment intensity is more predictive of posttraumatic stress in both child and young adult survivors than that of objective rating of these parameters by medical professionals.^{5 - 7} The perception of risk and the subjective assessment of health status may determine the survivor's ability or desire to integrate into society, to interact with the medical care system, and may inform his or her approach to risk-taking behaviors and preventive health.

Survivors of childhood cancer often respond to their perceived risk in ways that are beneficial. They are less likely to engage in risky behaviors, including smoking, recreational drug use, and excessive alcohol use.^{8 - 10} With universal access to health care, as in one UK program, the majority of survivors (84%) returned for prescribed follow-up care and 15% attended additional clinics for specialty care related to the diagnosis.¹¹ Mild levels of posttraumatic stress may promote vigilance with health care recommendations and may discourage high-risk behaviors.⁵ Survivors of childhood cancer often report better quality of life than do controls, an outcome sometimes attributed to denial^{12 - 13} that also may reflect an enhanced appreciation of life after therapy, despite adverse effects on actual health status.

Assessment of perceived health status of survivors provides information that may be missed by standard medical evaluation. The data in the study by Hudson et al³ regarding patients with Hodgkin disease provide an example. Although they had the least functional impairment and minimal activity limitation, the perceived health status of survivors of Hodgkin disease was better only than that of patients with central nervous system tumors, who have been shown to have profound cognitive and neuroendocrine deficits.¹⁴ This unexpected result necessitates inquiry into potential cause. Fatigue, reported in 42% of survivors of Hodgkin disease in a study by Fobair et al,¹⁵ may play a role in the perception of adverse health. Further investigation is needed to determine if fatigue is caused by an unrecognized physiologic abnormality. Alternatively, exposure of patients with Hodgkin disease to information about increased risk of breast cancer,¹⁶ secondary malignancy,¹⁷ and myocardial ischemia¹⁸ may engender a sense of poor health. The report of adverse health status may reveal appropriate concern about health risk rather than ill health.

Analysis of disease-specific effects that influence adverse outcomes is facilitated by the large cohort size in the study by Hudson et al.³ Patients with bone tumors are among the most severely affected in the domains of activity limitation, functional impairment, and pain. Activity limitation was the most common effect because amputations or limb salvage procedures are required. Patients with central nervous system tumors also have enhanced functional impairment and activity limitations, yet functional impairment is most prevalent as is expected with the extreme cognitive impairment known to affect quality of life in survivors of brain tumors.¹⁹ Cognitive effects are significantly more limiting than physical effects in the integration of cancer survivors into mainstream society.²⁰ Such findings highlight groups most in need of interventions and thus could influence determination of resource allocation.

The cohort size in the study by Hudson et al³ allowed assessment of adverse outcomes of specific therapeutic interventions (radiation, alkylating agents, anthracyclines) and their cumulative doses, thereby providing information for counseling patients and for modifying new treatment regimens. Age-specific effects were evident. Enhanced anxiety and adverse general health in those survivors treated as adolescents were reflected in outcomes of Hodgkin disease, bone tumors, and sarcomas. Since Hodgkin disease has a more than 90% survival rate with outpatient treatment regimens, better outcome would have been expected if perceived risk was based on treatment factors alone. The perception of risk is likely to influence not only the cancer-related anxiety/fears and the mental health domain of health status, but also the overall view of general health, functional status, and potentially pain and activity levels.

Physical effects often are less relevant to quality of life than are psychological and social aspects.²¹ For childhood cancer survivors, medical issues compound the developmental task of transition to adult life. Concerns of health risk influence self-image and outlook on life,²² affecting function at all levels, particularly those that lead to social independence and integration (friendship, marriage, education, occupation). Assessment of quality of life is a measure of "individuals' perceptions of their position in life in the context of the culture and value system in which they live and in relation to their goals, standards, and concerns."²³ Langeveld et al²⁴ reviewed 30 studies of quality of life in young adult cancer survivors that included physical, psychological, social, and sexual functioning, noting that most pediatric cancer survivors had good quality of life. Educational deficits after cranial radiation, job discrimination, difficulty obtaining health and life insurance, and concern about reproductive capacity or health of offspring also were noted.

Programs to assist adult survivors with long-term concerns may be difficult to find, even for those who have maintained a nexus to the treatment center. Clinicians working in children's hospitals may not be allowed to care for patients older than 18 years. Pediatric oncology programs may continue to provide care to patients beyond age 30 years simply because no community resources are available for care by individuals knowledgeable about pediatric cancer therapy. Few internists or family practitioners work directly with pediatric follow-up programs. In a study by Oeffinger et al,²⁵ only 53% of the pediatric national cooperative trials institutions reported the existence of follow-up programs for childhood cancer survivors, and rarely was there involvement of an adult oncologist (13%) or a primary care physician (8%). Kadan-Lottick et al²⁶ surveyed participants in the Childhood Cancer Survivor Study cohort (from which the study by Hudson et al³ also derives) and found that only 44% of patients had attended a long-term follow-up program.

In addition to determining appropriate follow-up care, studies must be developed to enhance understanding of long-term outcomes of new treatments, perhaps through the Children's Oncology Group (the pediatric cooperative trial group).²⁷ Although these trials often aim to reduce toxic effects by limiting chemotherapy, deleting radiotherapy, or adding a protective agent in appropriate cohorts, study end points are usually based only on event-free survival. To determine whether a specific intervention effectively reduces an adverse outcome, study design must ensure adequate statistical power for the analysis. Mechanisms to capture the late outcomes become critical.

Minimal resources are available for long-term programs for survivors of childhood cancer in the United States, despite a need that grows daily with the continued increase in survivors. Evaluation of cancer survivors is time consuming and not fully reimbursable. Refusal by insurers to allow access to the original treatment center and to standard screening tests for long-term sequelae is commonplace. Programs that do exist in pediatric oncology divisions usually rely on philanthropic support or fiscal resources derived from cancer therapy reimbursements. Research support is rare, even with the multitude of incompletely understood issues.

Support is necessary to develop and sustain programs that have expertise in the effects of pediatric cancer therapy on the developing child and in young adult survivors. Countries with socialized medicine often provide resources as a standard of care,²⁸ but comparable mandates do not exist in the United States. Most survivors of childhood cancer will function well, having the potential for decades of participation in society as healthy, productive adults. Access to appropriate screening and counseling will mitigate the risks, and in the long run reduce the costs to the individuals and to society. It is essential to support young patients as they mature, to help them understand risks and to optimize their health status, potentially for an ensuing 4 to 5 decades of survivorship. With approximately 200 000 young adult survivors now in the United States, this effort may enhance almost 10 million cumulative years of life.